Contemporary Reviews in Cardiovascular Medicine Inflammation in Peripheral Artery Disease

Peripheral artery disease (PAD), which consists of partial or complete obstruction of the arteries in the lower limbs, is one of the most common manifestations of atherosclerosis, affecting 27 million individuals in Europe and North America.1 Its main symptomatic expression, intermittent claudication, was first described by the French veterinarian Bouley2 in a horse affected by progressive limping and lameness consequent to a fibrous clot that occluded the femoral arteries of the posterior limbs. In humans, this condition was noted by Brodie3 in 1846, but it was Charcot4 who in 1858 clearly defined and described the syndrome (and used the term “intermittent claudication”).3,4 Reproducibly elicited by walking-induced muscle ischemia and consistently relieved by rest that allows reperfusion of the affected limb, intermittent claudication may be considered “leg effort angina.” Indeed, for a long time, treatment was aimed exclusively at relieving leg symptoms and improving the functional status of affected individuals. However, in the 1950s, Stammers5 and Allen et al6 independently observed that patients with claudication were at high mortality risk. Subsequent prospective studies confirmed that patients with PAD rarely progress to limb loss but that the presence of PAD is a powerful and independent predictor of cardiac and cerebral ischemic events.7–11 However, this increased risk appears to be poorly related to classic risk factors, suggesting that once PAD is established, subsequent cardiovascular risk is related to the severity and extent of the underlying atherosclerotic disease and possibly other factors.7–11 It is well established that hypertension, smoking, diabetes mellitus, and hypercholesterolemia play a major role in the initiation and development of atherosclerosis and its clinical manifestations, although the prognostic potency of each of these factors in atherogenesis differs in the various arterial beds. As early as 1815, the year that cholesterol was discovered although not yet correlated to atherosclerosis, the London surgeon Joseph Hodgson published a monograph on vascular disease in which he cited inflammation as the underlying cause of atherosclerosis.12,13 In 1858, the German pathologist Rudolf Virchow14 found inflammatory cells in vascular plaques, but it was Sir William Osler15 who, in 1908, implicated inflammation and infection in the pathogenesis of atherosclerosis. However, the inflammation hypothesis was ignored for nearly a century, during which time atherosclerosis was firmly believed to be a cholesterol disease. The causative role of inflammation in the atherogenic process was established only at the end of the last millennium when many lines of evidence suggested alternative mechanisms to the cholesterol theory, and Russell Ross16 branded atherosclerosis an inflammatory disease. In actual fact, atherosclerosis is not simply a disorder of pathological lipid deposition but is regarded as a dynamic and progressive pathophysiological process arising from a combination of endothelial dysfunction and inflammation interacting with the standard risk factors that contribute to the initiation, clinical manifestations, and cardiovascular risk of all atherosclerotic diseases.17,18 Endothelial dysfunction in PAD has been discussed previously.18 The present review is devoted to the role played by inflammation in PAD, summarizing the data showing that increased levels of inflammatory markers are associated with the development of PAD, its cardiovascular comorbidity, and risk of developing cardiac and cerebrovascular ischemic events. The final part of the review describes the inflammatory mechanisms presumed to contribute to claudication and its severity.